Oxytocin is released in socially-engaged contexts, while ARGININE VASOPRESSIN has predominantly an anxiogenic effect. Our goal was to evaluate the effects of both OXYTOCIN and ARGININE VASOPRESSIN on verbally-induced analgesia using a well-established model of top-down modulation of pain. Much of our knowledge regarding the regulatory function of OXYTOCIN and ARGININE VASOPRESSIN of pain and social interactions arises from animal studies using central administration of agonists and antagonists or knockout models. Despite its social, anxiolitic/anxiogenic and likely, analgesic effects, there remains a need to understand the role of OXYTOCIN and ARGININE VASOPRESSIN in the modulation of placebo-induced analgesia in humans. We recruited 108 (54 men, 54 women) healthy participants and we determined the role of OXYTOCIN and ARGININE VASOPRESSIN neuropeptides whose function has been associated with the processing of social cues (Insel 2010; Meyer-Lindenberg et al. 2011) in expectancy-induced analgesia. We used a double-blinded between-subject design in which healthy subjects were assigned to a single acute administration of either: 1) intranasal oxytocin, 2) intranasal arginine vasopressin, 3) intranasal placebo, or 4) no-treatment. Our findings support the fact that verbally-induced placebo analgesia can be pharmacologically modulated. OXYTOCIN increased pain tolerance but did not change placebo analgesia. Conversely, ARGININE VASOPRESSIN agonists induced an increase in the magnitude of placebo analgesia as compared to no-treatment, placebo, and oxytocin. Heart rate changes observed under ARGININE VASOPRESSIN treatment show an opposite trend as compared to the effects induced by oxytocin, placebo and no treatment. A similar modulatory effect of ARGININE VASOPRESSIN was observed for the skin sympathetic responses and salivary cortisol that shows less of a decrease under ARGININE VASOPRESSIN as compared to placebo and OXYTOCIN treatments. Anxiety increased under ARGININE VASOPRESSIN. Our findings suggest that the VASOPRESSINergic system influences placebo analgesia by modulating stress responses. These effects indicate a dynamic interplay between anxiety, stress and verbally-induced analgesia (Colloca et al., in preparation). We collected and have started to extract the DNA from all the participants enrolled in the pharmacological part and fMRI study. For each participant in Experiments 1 and 3, we will obtain the genotypes of each candidate polymorphism. For each participant the phenotypic outcomes consist of pain and cortisol changes. We use genotype-phenotype association statistical tests to measure the association between the polymorphisms and outcomes. We also test for linear and quadratic effects of treatment (placebo, OXT, AVP and no-treatment) and gender. Finally, we have begun the fMRI study. The procedure consists of repetitive exposure to different stimuli. Visual stimuli comprise a set of nonsocial (green, red and yellow lights) and a set of social cues consisting of pictures from the Ekman FEEST stimulus battery. On Day 1, subjects learn through a conditioning paradigm (100% contingency) that each colored cue predicts different heat stimulation intensities consistently. Heat stimulation will be delivered at a warm, non-painful temperature, medium and moderately high painful temperature. Faces of actors expressing fear, happiness, or no emotions (neutral) are shown concurrent with the levels of heat stimulation. The color-face pairings are designed to enhance the expectation of pain and no-pain. After the conditioning behavioral phase, the heat stimulation will be set at a medium level in association with the visual stimuli. According to a partial probabilistic reinforcement strategy, during the task performed in the MRI, the concurrent face feedback is reversed (relative to conditioning), such that subjects will experience a face prediction. We have obtained approval by the NIMH Scientific committee, the White Panel IRB, the MRI safety Committee and we have completed the set up starting the fMRI data collection.